Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase

Mikhail Krasavin; Raivis Žalubovskis; Aiga Grandāne; Ilona Domračeva; Petr Zhmurov; Claudiu T Supuran

doi:10.1080/14756366.2020.1712596

Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase

J Enzyme Inhib Med Chem. 2020 Dec;35(1):506-510. doi: 10.1080/14756366.2020.1712596.

Authors

Mikhail Krasavin¹, Raivis Žalubovskis^{2

3}, Aiga Grandāne², Ilona Domračeva², Petr Zhmurov¹, Claudiu T Supuran⁴

Affiliations

¹ Department of Chemistry, Saint Petersburg State University, Saint Petersburg, Russian Federation.
² Latvian Institute of Organic Synthesis, Riga, Latvia.
³ Faculty of Materials Science and Applied Chemistry, Institute of Technology of Organic Chemistry, Riga Technical University, Riga, Latvia.
⁴ Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy.

Abstract

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and - hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.

Keywords: Anticancer agents; carbonic anhydrase inhibition; hypoxia; oxidative stress; thioredoxin reductase inhibition.

MeSH terms

Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrases / metabolism*
Cell Proliferation / drug effects
Cell Survival / drug effects
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
MCF-7 Cells
Molecular Structure
Structure-Activity Relationship
Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
Thioredoxin-Disulfide Reductase / metabolism
Tumor Cells, Cultured

Substances

Antigens, Neoplasm
Antineoplastic Agents
Coumarins
Enzyme Inhibitors
Isoenzymes
Thioredoxin-Disulfide Reductase
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII

Grants and funding

This work was supported by the Russian Foundation for Basic Research (project grant 18-515-76001) as well as by ERA.Net RUS plus Joint Programme grant RUS_ST2017-309 and State Education Development Agency of Republic of Latvia (“THIOREDIN”). AG is grateful to European Regional Development Fund (ERDF, project no. 1.1.1.2/VIAA/1/16/235). PZ is indebted to Saint Petersburg State University for providing his postdoctoral fellowship.